It has been known for many years that insulin can be successfully co-crystallized with zinc ions to obtain numerous types of stable crystals with longer time actions than soluble or amorphous, uncrystallized insulin. In the early 1950s, a new formulation of beef insulin crystals was developed which contained only insulin and zinc in an acetate buffer at neutral pH. Hallas-M.o slashed.ller, et al., Science 116, 394-398 (1952). This insulin preparation avoided phosphate ions, which interact strongly with zinc ions to form insoluble zinc phosphate derivatives. Formulations containing only the crystalline insulin in acetate buffer are called Ultralente. Crystals prepared in this manner will be referred herein as Ultralente crystals.
Recently, monomeric insulin analogs have been developed that retain the biological activity of native human insulin but are less prone to dimerization and self-association to higher molecular weight forms. This lack of self-association results in a comparatively more rapid onset of activity. These insulin analogs provide a rapid absorption to place injection time and peak action of insulin into closer proximity with postprandial glucose excursion associated in the response to a meal.
The present invention provides formulations of a monomeric insulin analog that have a protracted effect. Because monomeric insulin analogs do not aggregate and associate like insulin, it is quite remarkable that stable, analog crystals may be formed. Surprisingly, the formulations of the present invention offer a predictable, extended duration of action.